An increased level of angiotensin-II (AngII), as is found in heart failure, is associated with an increased risk of ventricular tachycardia (VT), and treatment with angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor blockers reduces that risk (References 1 and 2). Investigating the mechanisms of AngII-induced arrhythmia may result in finding new antiarrhythmic targets. We created a mouse model of cardiac-restricted angiotensin converting enzyme (ACE) overexpression (Reference 3). We demonstrated that homozygous mice (ACES/8) have a high rate of sudden cardiac death (SCD), with telemetry monitoring showing that approximately 80% of the SCD resulted from VT and less commonly severe bradycardia (Reference 4). The VT and bradycardia were the result of c-Src tyrosine kinase activation, connexin43 (Cx43) reduction, and the impairment of gap junction conduction (References 4-6).
Excess amounts of reactive oxygen species (ROS) have been implicated in the genesis of arrhythmia (References 7-11). The level of ROS is elevated in ACE8/8 mice (Reference 5). ROS is known to activate c-Src (Reference 12). We sought to determine whether ROS mediated any of the Cx43 remodeling during renin-angiotensin system (RAS) activation. Despite considerable evidence that oxidative stress is arrhythmogenic, conventional antioxidants such as vitamin E have not produced impressive therapeutic results in clinical trials (Reference 13). The sources of ROS include the nicotinamide adenine dinucleotide phosphate (NADPH) oxidase activated by AngII and generally requiring the p67 subunit for activity, xanthine oxidase, uncoupled nitric oxide synthase (NOS) in part because of tetrahydrobiopterin depletion, and mitochondria (Reference 14).
In the present invention, the inhibitor therapies were tested to determine the major source of cardiac ROS contributing to arrhythmogenesis in ACE8/8 mice.